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R Lord

Publications and source records attributed to R Lord.

At least 55 records · Page 3Linked to original sources
PubMed1997

The characterization of reconstituted passenger leukocytes on the induction of tolerance in rat liver transplantation.

The tolerance induced by orthotopic liver transplantation [DA (RT1a) rats to PVG (RT1c) rats] can be prevented by total body irradiation of the donor rat. Reconstitution of the irradiated donor with DA splenic leukocytes reintroduces this tolerance. To investigate the major histocompatibility complex (MHC) specificity of passenger leukocytes, irradiated DA donors were reconstituted by third-party BN (RT1n) splenic leukocytes. The reconstitution with BN splenocytes re-established DA-specific tolerance in PVG recipients, as confirmed by subsequent DA cardiac allografting, while BN hearts were rejected with second-set tempo. To determine which cell components play an important role in re-establishing liver graft tolerance, DA splenic leukocytes were further purified into three types: T, B, and adherent cells. Only "T-cell-enriched" preparations restored liver graft tolerance in three out of five PVG recipients. These results suggest that passenger leukocytes of differing MHC types can help to induce liver-specific tolerance and that T cells in the liver graft may be essential to regulate tolerance induction.

Animals↗
PubMed1997

Conversion from cyclosporin to tacrolimus in a patient with prolonged acute tubular necrosis.

Acute tubular necrosis (ATN) is a common condition of following cadaveric renal transplantation with an incidence in many series of nearly 50%. The aetiology is uncertain; however, it would appear to be related to damage to the transplant kidney either prior to retrieval, During cold preservation or during re-warming of the kidney at the time of anastamotic construction. There is no specific therapy for ATN and treatment is comprised of an expectant policy with supportive dialysis and fluid restriction. Renal function improves in the majority of cases, though there may be delayed function for several weeks. We report a case of dialysis-dependent ATN that had persisted for 5 months following transplantation. Following conversion to tacrolimus there was immediate improvement in renal function, and after a month of tacrolimus therapy the patient was dialysis-independent.

Adult↗
PubMed1997

The prevention of graft-versus-host disease by the serum of liver retransplanted rats.

The effect of serum from orthotopic liver retransplanted rats (re-OLT serum) on graft-versus-host disease (GVHD) was studied in rats. In the re-transplantation model of rat liver, orthotopic liver transplantation (OLT) was carried out in the DA (RT1a) into PVG (RT1c) combination; two days later the DA liver was removed and a new PVG liver implanted into the same recipient (re-OLT). In the in vivo GVHD model, male PVG rats were sublethally irradiated and injected intravenously with 3 x 10(8) DA or BN (RT1n) spleen through the penial vein. Within 1 h of the inoculation, rats of the experimental group were injected with 1 ml of re-OLT serum taken at postoperative day (POD) 7. Rats in the control group received 1 ml of normal PVG serum or syngeneic re-OLT serum (PVG-PVG, PVG-PVG). All PVG rats in the control groups died of GVHD within 21 days after the inoculation of DA or BN spleen lymphocytes. However, when the animals were treated with re-OLT serum, 100% (6/6) of the rats survived more than 60 days, following inoculation with DA lymphocytes but not with BN lymphocytes. The POD 7 re-OLT serum showed a strong inhibition against DA anti-PVG mixed lymphocyte reaction (MLR), although re-OLT serum did not contain soluble DA class I antigens, anti-DA class I or II antibody. The potential GVHD inhibitory factors in re-OLT serum may be two unique immunosuppressive proteins, which have been detected by SDS PAGE and reported previously. We conclude that re-OLT serum has immunosuppressive factors, which, at least in part, prevented the induction of GVHD in rats.

Animals↗
PubMed1997

Differences in the rate of donor leucocyte migration between natural and drug-assisted tolerance following rat liver transplantation.

The number involved in and the rate of migration of donor leucocytes into the following recipient organs (spleen, thymus, bone marrow, lung and mesenteric lymph nodes) were measured in two rat models of orthotopic liver transplantation (OLT) using donor-specific MHC class I antibodies. The first OLT model is one that does not require immunosuppression in order to achieve tolerance and involved the transplantation of DA (MHC haplotype, RT1a) livers into PVG (RT1c) recipients. The second model was one that required a 7-day (10 mg/kg) treatment with cyclosporin A (CsA) to achieve tolerance and used DA donors into Lewis (RT1(1)) recipients. Recipient organs were biopsied on days 3, 20 and 87 following OLT and donor leucocyte migration was quantified by immunohistochemistry and computer densitometry of immunoblots of detergent-solublized tissues in order to resolve both membrane-bound and soluble donor MHC class I antigen. In a separate experiment, spleen biopsies were taken following OLT on days 3 and 15 from the naturally tolerizing OLT model (DA into PVG), treated with and without CsA for 7 days and compared with the (DA into Lewis) model. The initial rate of leucocyte migration between days 3 and 21 following OLT was found to be the most rapid into the spleen, followed by the bone marrow and mesenteric lymph nodes in the naturally tolerant (DA into PVG) model when compared with the (DA into Lewis) model. The number of donor leucocytes in the spleen and mesenteric lymph nodes in both models was, however, approximately the same by 87 days. No real difference in the rate of leucocyte migration was seen in the thymus or the lung for both transplant models over the time course assayed. CsA was found to lower the rate of donor leucocyte migration only over the period it was administered. The rate of donor leucocyte migration into the spleen was still much lower 15 days after OLT in the (DA into Lewis) model compared with the (DA into PVG) model treated with and without CsA. Thus the differences in the rate of donor leucocyte migration into the spleen, bone marrow and mesenteric lymph nodes immediately following OLT may offer an explanation as to why the (DA into PVG) combination is able to accept a transplanted liver without immunosuppressive therapy.

Animals↗
PubMed1997

Abdominal wall hernia in autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal impairment with a number of well recognized extrarenal associations. A high incidence of abdominal wall hernia was noted in patients with ADPKD. METHODS: A retrospective review of the notes of all patients with ADPKD on the South Wales renal replacement therapy database was performed. These patients were compared with age- and sex-matched patients with renal failure but without ADPKD and with general surgical patients. RESULTS: The prevalence of hernia in patients with ADPKD was 38 of 85 (45 per cent) compared with seven of 85 (8 per cent) for other forms of renal failure and three of 85 (4 per cent) for general surgical controls (P < 0.001). There were significantly greater numbers of inguinal (P < 0.001), incisional (P = 0.019) and paraumbilical (P = 0.007) hernias in patients with ADPKD compared with the other two groups. CONCLUSION: These results show a significantly greater incidence of hernia, which could be an additional manifestation of the underlying defect in extracellular matrix production identified in patients with ADPKD.

Adult↗
PubMed1996

Novel immunosuppressive proteins purified from the serum of liver-retransplanted rats.

Liver grafts between certain rat strain combinations, such as DA (RT1a)-into-PVG (RT1c), are accepted without the use of immunosuppressive agents. To explore the nature and role of serum proteins in liver-induced immunosuppression, we have developed a retransplantation model of rat liver grafting. In this procedure, orthotopic liver transplantation (OLT) is carried out in the DA-into-PVG combination; two days later the DA liver is removed and a new PVG liver implanted into the same recipient (re-OLT). Serum from re-OLT rats was immunosuppressive when tested in mixed lymphocyte reactions (MLR). Three novel proteins were detected in re-OLT serum by SDS-PAGE, with sizes of 180 kD, 87 kD, and 10 kD. The N-terminal sequences of these were distinct and did not match protein sequences in the computer databases, although there was some homology between the 10 kD sequence and the beta-chain of rat hemoglobin. Purified 87 kD and 10 kD proteins were immunosuppressive in MLR; in both cases suppression was dose-dependent and nonstimulator-specific. Production of the 180 kD and 87 kD molecules required the presence of the recipient spleen. We conclude that re-OLT serum contains novel immunosuppressive proteins, which may be products of immune recognition and associated with the immediate termination of graft rejection.

Amino Acid Sequence↗
PubMed1996

Restoration of tolerance to rat hepatic allografts by spleen-derived passenger leukocytes.

The tolerance induced by orthotopic liver transplantation (OLT) in certain combinations of rat strains can be prevented by total body irradiation (TBI) of the donor. We demonstrate here that the intravenous inoculation of splenic leukocytes into irradiated donors before OLT could re-establish tolerance in association with a state of microchimerism detected in the recipients. When donor DA (RT1a) strain rats were irradiated with 1000 rad 24 h before liver harvesting and subsequent liver implantation into PVG recipients, five out of six rats died from rejection in this normally tolerogenic OLT (DA-PVG) combination. Injection of 1.5 x 10(8) splenic leukocytes from naive DA rats into the irradiated DA donor rats 24 h before OLT restored the tolerogenic potential of the liver allografts. Immunofluorescence assay revealed an increased number of donor (DA) type cells in the PVG recipient bearing a repopulated DA liver, compared to the PVG recipient of an irradiated liver. These results suggest that passenger leukocytes reconstituted by splenic leukocytes have the capacity to protect liver allografts.

Animals↗
PubMed1996

The beneficial effect of the prostacyclin analogue (OP 2507) on rat liver transplantation subjected to an extended anhepatic phase.

We investigated the effect of a prostacyclin analogue (OP 2507) on PVG (RT1c) recipients subjected to an extended anhepatic phase (AH) and transplanted orthotopically with PVG livers. All of the animals that underwent orthotopic liver transplantation (OLT) with a 20-min AH survived for 1 week with or without OP 2507, (OP) treatment (10/10, 100%). When the AH was lengthened to 45 min, the 1-week survival rate of recipients was poor in the OP-untreated groups (1/10, 10%). Treatment of the recipient with OP 2507, 0.15 micrograms/kg per minute for 30 min, prior to the 45-min AH substantially improved 1-week survival (5/6, 83.3%, P < 0.05). The serum TNF-alpha level at day 1 in OP-treated animals that underwent OLT with a 45-min AH was significantly lower than that in animals with 45-min AH OLT without OP treatment. We conclude that OP 2507 treatment has potential usefulness as a perioperative treatment when the AH is extended during OLT.

Animals↗
PubMed1996

Effect of context and adjuvant on the immunogenicity of recombinant proteins and peptide conjugates derived from the polymorphic malarial surface antigen MSA2.

We have identified a 51 kDa glycosylated myristylated merozoite surface antigen (MSA2) as the target of a number of monoclonal antibodies which inhibit in vitro invasion of the human malarial parasite Plasmodium falciparum. This antigen has been shown to exist in a limited number of strain specific forms but despite wide variation in the sequences of the internal repeat regions both N and C terminal elements of the protein are almost totally conserved. Accordingly, we prepared a large number of overlapping peptide constructs and demonstrated that one peptide SNTFINNA (E71) from the N terminus and two peptides, QHGHMHGS (G5) and NTSDSQKE (G12) from the C terminus could, when suitably conjoined to the carrier protein diphtheria toxoid (DT), elicit antibodies reactive with MSA2 from diverse strains of P. falciparum. Here we compare the immunogenicity of these peptide constructs with two recombinant proteins containing the entire amino acid sequence of MSA2 from the FCQ-27/PNG strain (1609) and the 3D7 strain (1623). We have formulated these recombinant and peptide antigens with Freund's adjuvant, Alum and Algammulin. Both recombinant and peptide antigens elicit high titre antibodies when tested by ELISA against the immunogens themselves. Although both recombinant proteins include the constant region peptide sequences E71, G5 and G12, the extent of ELISA cross reaction between antibody raised against recombinant and peptide antigen or antibody raised against peptide and recombinant antigen is small and sporadic, and depends to an extent on the adjuvant employed. Antisera against both recombinant proteins 1609 and 1623 detected either recombinant on Western blots, as well as detecting native MSA2 in whole protein extracts from both FCQ-27/PNG and 3D7 strains. Antisera against peptide construct E71 recognized recombinant 1609 but not 1623 but recognized the native MSA2 in both strains studied. Antisera against peptide construct G5 showed a similar pattern of recognition but also detected recombinant 1623 on Western blotting. These results emphasize the importance of context and adjuvant on the ability of selected immunogenic epitopes to elicit antibodies appropriately directed against the native antigen.

Adjuvants, Immunologic↗
PubMed1996

Allograft acceptance and rejection, mediated by a liver suppressor factor, LSF-1, purified from serum of liver transplanted rats.

In certain rat strain combinations liver allografts are spontaneously accepted without immunosuppression and induce donor-specific tolerance to further skin and heart graft in the recipient. Such an effect is also transferrable using serum from orthotopically liver transplanted rats (OLT serum). In the OLT serum of one such combination, DA (RT1a) donor into PVG (RT1c) recipient, a 40 kDa protein (liver suppressor factor, LSF-1) has been identified and shown to be immunosuppressive in vitro. The aim of the present study is to investigate the immunological effect of LSF-1 and a polyclonal antibody (anti-LSF-1) against this molecule, in a rat heterotopic heart transplant (HHT) model and OLT model, respectively. Intramuscular injection of 300 micrograms of LSF-1, 1 h postoperatively, into a PVG recipient of either a DA or BN (RT1n) cardiac allograft caused significant prolongation of graft survival. Intravenous injection of polyclonal rabbit sera raised against an N-terminal peptide of LSF-1 (anti-LSF-1), within 1 h postoperatively, had variable effects on the survival of DA liver grafts in PVG recipients. In 5/6 cases injection of between 1 and 2 ml of anti-LSF-1 resulted in death of the recipient. Histological examination of the liver showed severe rejection with lymphoid cell infiltration of the portal tract and sinusoids and extensive damage to the parenchyma. All control rats survived for more than 60 days without any signs of rejection. The anti-LSF-1 polyclonal antibody prevented the injection of tolerance in the normally tolerogenic model (DA into PVG). This, together with the in vivo results, suggests a role for LSF-1 in the induction of tolerance.

Animals↗
PubMed1996

Cytomegalovirus involving gastrointestinal tract in renal transplant recipients.

Infection due to cytomegalovirus (CMV) is a substantial cause of mortality and morbidity among renal transplant recipients but the prognosis of the disease has changed dramatically since the introduction of ganciclovir (GAN). During a period of 5 years we treated 54 patients who developed CMV disease. From this group of patients we identified 7 patients with primary gastrointestinal tract (GIT) CMV disease who received treatment with GAN. Tissue diagnosis was made by endoscopy of the upper GIT (6 patients) or sigmoidoscopy (one patient) and histological examination. All patients improved after treatment with GAN; three patients required additional treatment for recurrent CMV disease and recovered, and 1 patient relapsed without GIT involvement (P = 0.014). Recurrent CMV disease was more severe (mean score of 15 in relapse compared to 7 in the first episode). We believe relapse to be more common and the disease to be more severe in the presence of GIT involvement suggesting that a longer duration of treatment with GAN may be required in this clinical manifestation of CMV disease.

Adolescent↗
PubMed1996

Powerful immunosuppression by a new 40-kd serum protein (KX-5) induced by liver transplantation.

The presence of novel immunosuppressive proteins in the serum of liver grafted rats is associated with the induction of tolerance. This may provide part of the explanation for the induction or maintenance of tolerance in this liver graft mode, although their relationship to the antigen-specific aspects of liver graft survival (clonal deletion of T cells, release of soluble class I antigen, production of anti-class II antibodies) remains to be investigated. The KX-5 protein was nonspecifically immunosuppressive in vivo, suggesting the possibility of harnessing the tolerogenic properties of liver grafts in a soluble form for clinical application.

Animals↗
PubMed1995

Orthotopic liver retransplantation in rats.

A surgical experience with a method of rate orthotopic liver retransplantation (OLRT), and a preliminary study of immunological responses after OLRT are reported. OLRT was performed on the same recipient after the fist orthotopic liver transplantation (1st-OLT) according to our original (Kamada's) cuff method. Replacement of the portal vein (PV) and infra-hepatic vena cava (IHVC) cuffs was not technically difficult. However, there were no survivors from the first 6 retransplanted rats, mainly due to complications from defective supra-hepatic vena cava (SHVC) anastomoses. Unlike the human intra-abdominal SHVC, the posterior wall of the intra-abdominal SHVC in rats is too short and fragile to perform an end-to-end anastomosis twice between donor and recipient SHVC. For a second group of seven retransplants, a modification of the SHVC anastomosis was made between donor and recipient SHVC in conjunction with the recipient's cuff diaphragm. This enabled reanastomosis to be secure, resulting in the improved 1-week survival after isogenic OLRT (85.7%). This OLRT model has been applied to the fully allogeneic combination for several immunological studies and led to novel findings. Thus, an experimental model of a rat orthotopic liver retransplant model has the potential to allow more valuable insights into the immunological study of chronic rejection, sensitization and chimerism following liver retransplantation.

Anastomosis, Surgical↗
PubMed1995

Absorption of a new oral formulation of cyclosporin A in a child on parenteral nutrition.

A 2-year-old child underwent renal transplantation in the presence of a post-viral enteropathy rendering him dependent on total parenteral nutrition. As part of his immunosuppression, he was given a new oral formulation of cyclosporin A (Neoral), which he was able to absorb satisfactorily, using conventional doses, during the 6 weeks he was dependent on intravenous nutrition and in the face of intermittent severe diarrhoea. An unusual pharmacokinetic profile was observed.

Administration, Oral↗